APPLICANT'S ABSTRACT: There is little doubt that drug abuse has become one of the most important problems facing our country today. The fallout of this problem includes increasing crime and destruction of the health of a significant portion of our population. At the present time one of the most fashionable as well as dangerous drugs in this country is cocaine. This substance is administered via "snorting" or by smoking the freebase form known as crack. The net effect of these drugs results in significant alterations in body function. Many of the frequently abused drugs, under specific conditions, are capable of interfering with immune responses. It has been demonstrated that when cocaine was injected, marked effects occurred on immune responsiveness, including macrophage (M0) function. Because of the multifunctional capability of these cells in both humoral and cellular responses, as well as our previous experience with macrophage activation, we intend to focus our efforts on the effects of cocaine on the function of murine macrophages. Cocaine will be given to experimental mice using the intraperitoneal route. The aims of the project are to ascertain the effects of cocaine and its metabolites on specific M0 functions including phagocytosis and activation to the cytotoxic state. This will include the measuring of M0 surface receptors associated with these functions as well as the production of cytokines which represent communication signals among cells. Disruption of the cytokine network can result in an altered immune response. The cytokines to be measured include interleukin 1, tumor necrosis factor, interferon and transforming growth factor B. Nuclear factor kappa B, which turns on cytokine genes, will also be evaluated. It is anticipated that data obtained in this study will be used to develop approaches to study other leukocytes so that a more complete picture can be obtained on the effects of cocaine on the immune system and its possible ramifications in triggering or exacerbating other diseases including AIDS. Relevance of these studies to AIDS progression relate to 1) possible direct effects of cocaine or its metabolites on HIV infected M0 or 2) indirect effects through modification of immune parameters.